Ubr1: A Protein Quality Control E3 Ubiquitin Ligase

描述（由申请人提供）：在细胞中进行蛋白质质量控制以限制错误折叠蛋白质的水平。它对正常细胞健康至关重要，是许多疾病的基础。质量控制（QC）的一个关键分支涉及泛素介导的错误折叠蛋白的蛋白质水解。我们最近发现，高度保守的E3泛素连接酶Ubr1在细胞质质量控制中具有先前未知的作用，通过Ubr1介导的泛素化降解异常蛋白。众所周知，Ubr1在“n端规则”中的作用，但新发现的Ubr1的QC功能独立于这些先前描述的动作。在细胞质质量控制中，Ubr1使用伴侣依赖的机制特异性地泛素化各种错误折叠的蛋白质。此外，Ubr1 QC通路在生理上是相关的，因为它是存活蛋白毒性细胞应激所必需的。在拟议的研究中，我们将使用遗传学，分子生物学和生化方法全面表征Ubr1在蛋白质质量控制中的作用和作用。这些研究涵盖了一系列问题，包括错误折叠蛋白底物的种类和特征，Ubr1质量控制功能所需的特征，伴侣在该途径中的作用，以及Ubr1介导的活细胞质量控制的生理功能。我们在ubr1介导的质量控制方面的工作具有医学意义，因为质量控制在我们社会一些紧迫疾病的病因学中很重要，而且因为UBR连接酶在所有真核生物中都是高度保守的。哺乳动物中UBR连接酶功能的丧失会导致许多有害的表型，包括导致严重的johnson - blizzard综合征的人类UBR1突变。我们认为，UBR泛素连接酶的质量控制作用将是其在所有生物体中许多方面功能的基础。我们的研究将定义这些功能，并最终找到利用或抑制它们的方法，以实现基本和生物医学利益。

DESCRIPTION (provided by applicant): Protein quality control operates in cells to limit levels misfolded proteins. It is critical for normal cell health and underlies many diseases. A key branch of quality control (QC) involves ubiquitin-mediated proteolysis of misfolded proteins. We have recently discovered that the highly conserved E3 ubiquitin ligase Ubr1 has a previously unknown role in cytoplasmic quality control, by which aberrant proteins are degraded by Ubr1- mediated ubiquitination. Ubr1 is well-known for its role in the "N-end rule", but the newly discovered QC functions of Ubr1 operate independently of these previously described actions. In cytoplasmic quality control, Ubr1 uses a chaperone-dependent mechanism to specifically ubiquitinate a wide variety of misfolded proteins. Furthermore, the Ubr1 QC pathway is physiologically relevant, since it is needed to survive proteotoxic cellular stress. In the proposed studies, we will completely characterize the action and role of Ubr1 in protein quality control, using genetic, molecular biological, and biochemical approaches. The studies span a range of questions, including the variety and characteristics of misfolded protein substrates, the features of Ubr1 required for its quality control function, the role of chaperones on the pathway, and the physiological functions Ubr1-mediated quality control the living cell. Our work on Ubr1-mediated quality control is medically relevant due to the importance of quality control in the etiology of some our society's pressing maladies, and because UBR ligases are highly conserved in all eukaryotes. Loss of UBR ligase functions in mammals causes many detrimental phenotypes, including the mutations of human UBR1 responsible for the severe Johanson-Blizzard syndrome. We believe that the quality control actions of UBR ubiquitin ligases will underlie many aspects of their function in all organisms. Our studies will define those functions and eventually the ways to harness or quell them for basic and biomedical benefit.